Bone tissue, or bone mass, contains high concentrations of calcium, usually in the form of hydroxyapatite, i.e., Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2. The hydroxyapatite is a finely divided, crystalline material which contains contaminating surface ions, such as CO.sub.3.sup.2-, Mg.sup.2+, and citrate, which alter its solubility.
Since bone is living tissue, it is constantly being remodelled. Certain bone cells, known as osteoblasts, promote bone formation. Other bone cells, known as osteoclasts, tend to cause bone dissolution. The process of biological calcification is critical in providing the mechanical strength for the skeleton and teeth. Pathological states associated with accelerated loss of bone mineral lead to diseases characterized by skeletal dysfunction and life-threatening metabolic disorders.
Hydroxyapatite, and the calcium of the bone generally exist in equilibrium with body fluids, particularly blood. Although the calcium and hydroxyapatite are soluble in blood, the equilibrium is maintained in healthy individuals, along with a stable and intact bone matrix.
Loss of bone mass from increased bone resorption results in accelerated loss of calcium into the blood. This is a major cause of illness, affecting millions of people in the United States. When significant depletion of bone calcium occurs and the structural integrity of the skeleton is compromised, several diseases result. An example of a diseased state associated with severe loss of bone mass would be osteoporosis, which is a major cause of hip and vertebral fractures in elderly, post-menopausal women. Hypercalcemia, or increased blood calcium concentration, occurs frequently in patients who suffer from hyperparathyroidism or cancer. This hypercalcemia can lead to kidney failure, coma, and death. Bone metastasis, or the spread of cancer cells into bone, occurs in patients who are resistant to cancer therapy, and causes progressive bone erosion, fractures, and excessive pain. All these conditions would be ameliorated by a drug which both decreases bone resorption and increases bone tissue calcium content.
The link between these diseases and the loss of calcium in bone tissue was discovered by investigating the calcium levels of blood and urine of patients who have these diseases. These patients usually had increased levels of blood and urine calcium, when compared to normal individuals. Studies with radiolabeled calcium showed that calcium is resorbed into the blood of patients with the aforementioned diseases at a rate that was much faster than expected.
Clearly, then, there has been a long-standing need for a treatment which would not only prevent resorption of calcium from bone but would also increase the rate of calcium accretion in bone.
It was found that gallium compounds, and gallium nitrate in particular, were effective in reducing excessive loss of bone calcium in humans. This method has been disclosed and claimed in applicants' copending application Ser. No. 622,726, the disclosure of which is incorporated by reference. There was no teaching until the present, however, of accretion of calcium and increased hydroxyapatite crystal formation and/or more perfect hydroxyapatite crystals.
Additional studies have since been undertaken to determine by what mechanism calcium is incorporated into human bone, and how this incorporation may be increased. In the course of these investigations, it has been discovered that various classes of compounds increase normal calcium content in bone tissue and reduce the amount of calcium which is resorbed by the blood. Bone calcification has been found to be increased if the solubility of the hydroxyapatite crystals of bone is reduced. Such an effect was achieved by increasing the size and/or perfection of hydroxyapatite crystals formed in the bone. An increase in the size and/or perfection of the hydroxyapatite crystals reduces their solubility, thereby resulting in this beneficial effect on bone.
It has been found that certain metal containing compounds act on bone tissue to cause increased bone calcium content, to increase the size and/or perfection of hydroxyapatite crystals, and to decrease the solubility of bone hydroxyapatite, all of which lead to increased bone strength. These metallic compounds increase the uptake of calcium by bones and retard the destruction of pre-existing bone tissue as a result of, various disorders, e.g.; metastasis of cancer tumors; hypercalcemia caused by cancer; parathyroid hormone or lymphokine related compounds; or increased bone cell resorbing activity.
Of particular interest in this regard are metal compounds which contain Group IIIa elements, especially gallium compounds such as gallium nitrate. The metallic compounds used have, of course, a low order of toxicity and are pharmaceutically acceptable. They are administered in sufficient dosages to be effective. The effective amount of the particular compound will vary, based upon the nature of the disease being treated, its severity, the age of the patient, and other factors which will be apparent to one skilled in the art.
The following particulars of the invention describe preferred aspects thereof. These particulars, however, should not be taken as limitations to the invention as described, but only of examples of particular, preferred embodiments.